Antihemorrhagic compound



Patented June 27, 1944 UNITED} STATES PATENT o-FFIc 2,35%5528ANTIHEMORRHAGIC oo P'oUNIi I Louis F. Fieser, Belmont,Mass.f,-as's'ig-nor to Re search Corporation, New York, N.-Y., acorpora-q tion of New York No Drawing. Application Julyl, 1939,

Serial'No. 2825427" 2 9 Claims.

This invention relates to certain new and useful improvements incompounds having antihemorrhagic activity and processes for theirproduction. Among such substances may be mentioned various derivativesof 1,4-naphthoquinone, particularly those having an alkyl or alkenylsubstituent in the 2-position and in which the 3- position containshydrogen or an alkyl or alkenyl radical and which may also containsubstituents in the benzene ring of the molecule, such as for instance:2,3-dimethyl-1,4-naphthoquinone, 2- allyl 1,4 naphthoquinone, 2.6-dimethyl 1,4 naphthoquinone, 2,7-dimethyl 1,4 naphthoquinone,3,7-dimethyl-2-allyl-1,4-naphthoquinone,

.2,3-diallyl-1,4-naphthoquinone, and 2,3-diallyl-6,7-dimethyl-1,4-naphthoquinone.

OtherlA-naphthoquinone derivatives in which the substituent in the 2-and/or 3-position is a long-chain radical are also of importance. Amongsuch may be mentioned the phytyl, farnesyl, cetyl, tetradecyl,octadecyl, and dodecyl derivatives.

'Such important derivatives of this character may be exemplified by thefollowing structure:

atives which are substituted in the 2'-position'with an alkyl or alkenylradical, the 3-position' being alkyl or alkenyl or hydrogen, and havefound that such new compounds exhibit anti-hemorrhagic properties inmuch greater degree than naphtho'quinone itself orits derivativesin'wliich either position 2 or*3 is substituted by a hydroxyl group. p

My findings in thisr'espect are further substantiated by the factthatfexperiments or tests with the known compoundslapachol, and lomamil,which are structurally related to p'hthio'c'ol,

have indicated that'the'se'latter substances like-' wise exhibit only aweak anti-hemorrhagic action in comparison with the alleyland allienylsubstituted compoundsdesc'ribed herein.

I have found that 2 ;3 -diinethyl-1,4-nalpltlth0 quinone;2-allyl-lA-naphthoquinona-2,3-diallyllA-naphthoqui-rione, and 2 ,3"dial1y'lj6 ,'7-d'imethyl-' l'fl-naphthoquinone exhibit; anti-hemorrhagicaction in pronounced degreed: r I a It has also been 'observed" t-h'a'th efZfi-and 2,1- dimethylderivatives of 1,4-r'i 1hthodt1inone ex hibitsome anti-hemorrhagic action.

The following examples are presented by way of illustration-of preferredembodiments of my invention, itbeing understood-however; thatvarions-modif cations maybe made without departing from the spirit andscope thereof.

(1) Z-all'yl-I ,4'-itaphthbquinone.fiA' diazo sdlu tion is prepared bydi'ssolving 2.3 g'. of su-l'faifilic acid d-ihydrate and 06 g. ofsodium'carbonate in '10 cc. of water,'cooling to 15, adding 0183 g.

a or sodium nitrite; -il'i 2 cc. of Water; and pouring the solution ontoa mixture of 2.3 cc. of concen trated hydrochloric acid and 13 1g. ofice.v The resulting suspension; after standing. at; 0 for fifteenminutes, is added to 'a' cooled solution prepared from 2.4 g. of Sodiumhydroxide, 1362.71 of water, and 2.02 g; of 2-allyl-l-naphthol'[prepared according to Claisen and'Eisleb, Ann, 401,

21 (1913) B. P. 140-144 at 4 After stand- 7 ing for one hour the deeppurple-red solution of the resulting azo compound is heated to 4050 andtreated with 5 g. of sodium hydrosulfite; added in 0.5 g. portions. Whenthe originalcolor is discharged and there is no further change, themixture is cooled in an ice bath and the-precipitate collected andwashedwith 1% sodium hydrosulfite solution. The slightly tanaminoallyl-naphthol is -dissolved by heating in alsolution of 1.4 cc. ofconcentrated hydrochloric acid and 0.45 .g. of stannous chloride in 17.5cc-Lof water and the filtered solutionis treated "with 2 cc. ofconcentrated hydrochloric acidandco'oled to 0.2-allyl-4-amino-l-naphthol"hydrochloride separates as colorless'needles,and isfwashedwith 6 N hydrochloric acid; the

of the theoretical). A sample was dried-for analysis at and 15 mm.pressures The salt is rather sparingly soluble in water.

For oxidation, 1 g. of the above hydrochloride is dissolved in 90 cc. ofwater containing 0.5 cc.

of concentrated hydrochloric acid and the solution is treated with 2.7g. of ferric chloride with decolorizing carbon, the solvent evaporatedand the residue crystallized from etherpetroleum ether. There isobtained 0.65 g. (76%) of 2-allyl-1,4-naphthoquinone in the form ofyellow needles, M. P. 36-36.5.

Anal.Calcd. for C13H1o02: c, 78.77; 14,509.

Found: C, 78.82; H, 5.14.

di'methyl-Z-allyl 1,4 naphthoquinone extracted with ether. The washedsolution is clarified with Norite, dried with sodium sulfate, and thesolvent removed in vacuum. The residue is taken up in petroleum ether(B. P. 20-40) and on cooling the quinone crystallizes as light yellowneedles, M. P. 42-425". Recrystallization from petroleum ether does notraise the melting point. The yield is 0.75 g. (57%). The properties aresimilar to those of the above described allyl compound.

Anal.-Calcd. for C15H14O2: 'C, 79.69; H, 6.24. Found: 79.82; H, 6.36.

(3) 2,3-diaZlyl-L4-naphthoquinone. Method a.-The; a-naphthohydroquinonerequired as starting material is prepared by dissolving 10 g.

of u-naphthoquinone in 50-75 cc. of hot alcohol and adding gradually asolution of 20 g. of stan- The substance is very readily soluble in mmzene, ether, and alcohol, less soluble in ligroin or petroleum ether,very sparingly soluble in water.

' The ultraviolet absorption spectrum in ethanol shows the followingmaxima: 246, 251 mu (log e=4.31) 332 m (log e=3.43) in hexane solutionthe most intense absorption band is clearly resolvable into two maxima(243, 251 my, log e,= 4.1), and there is a second intense band with amaximum at 260 m (log e=3.9) The quinone darkens rapidly in directsunlight.

(2) 3,7-dimethyl-Z-allyl-1,4-naphthoquinone. For the introduction of theallyl group, 5 g. of 2,6-dimethyl-8-naphthol [Weissgerber and Kruber,Ber., 52, 360 (1919)] is heated with stirring for15 hours with 3 g. ofallyl; bromide, 8 g. of finely-powdered potassium carbonate, and 75 cc.ofpurified acetone. The mixture is diluted with water, extracted withether, and after removing a trace of phenolic material by extraction ofthe ether layer with 10% alkali containing a little sodium hydrosulfite,the ethereal solution is dried and evaporated. The oil residue of crude2,6-dimethyl-8naphthol allyl ether is heated with 30 cc. of freshlydistilled dimethylaniline in an atmo'sphere of nitrogen for 2% hours ina, salt bath maintainedat 240 andthe cooled solution taken up in etherand extracted with dilute hydrochloric acid. The ethereal solution isthen extracted repeatedl with 10% potassium hydroxide solutioncontaining a trace of sodium hydrosulfite and Claisens mixture (aqueousalkali-methanol) and. the combined, filtered alkaline extracts areacidified andextracted with ether. After drying with sodium sulfate andremoving the solvent, the product (2,6-dimethyl-7-allyl-8-naphthol) isdistilled, B. P. 152-157 at 2 mm. The once distilled material is nearlypure and satisfactory for the next step.

Ana l.-Calcd. for 015E160: C, 84.86; H, 7.60. Found; C, 84.20; H, 7.74.

Coupling with diazotized sulfanilic acid is conducted as in Example 1and the crude 2,6-dimethyl-7-allyl-5-amino-8-naphthol collected as a;nearly colorless precipitate; yield,,2.3 g., The

substance is very sparingly soluble in the usual solvents and'dissolves' to only-a silght extent in boiling dilute hydrochloric acid(giving with exacid fine, colorless needles of the hydrochloride). Foroxidation, 13 g. ofthe free amine issuspended in 50 cc. of acetone, 30cc. of 0.7M ferric chloride solution (27 g. ferric chloride crystals and10 cc. of concentrated hydrochloric acid dilutedto 245 cc.) isadded,andon warming and stirring the' solid goes into solution" (1,0-15

minutes). The dark yellow solutionisijcool'ed,

diluted with 500 cc, of water and the oily 3,7-

nous chloride crystals and 20 cc. of concentrated hydrochloric acid in50 cc. of water. After heating gently until the color fades to paleyellow and filtering if necessary, the solution is diluted with water tothe point of saturation and cooled in an ice bath. The product separatesas colorless or slightly gray needles; yield 8.2-8.8 g.

Allylation is conducted as in Example 2, using 6.1 g. ofa-naphthohydroquinone, 6.5 cc. of allyl bromide, 10.4 g. of potassiumcarbonate, and 20 cc. of acetone, and refluxing for 10-15 hours. Afterdilution with water the product is taken up in ether and the rather darksolution extracted with water and with dilute alkali containing sodiumhydrosulfite. The solution is dried with magnesium sulfate,concentrated, and cooled to 78. The a-naphthohydroquinone diallyl etherproduced separates from the well cooled solution as a pasty solid, andafter adding a little petroleum ether this can be collected byfiltration. An additional quantity of the ether can be obtained from thefiltrate after diluting this with petroleum ether and clarifying it byfiltration through a tower of activated alumina, followed 'byconcentration and cooling to 78. The yield of material satisfactory forthe next step is 1.5-3.5 g. Repeated crystallization from petroleumether containing a trace of ether gives colorless plates, M. P,49.6-50.1".

AnaZ.-Calcd. for Ciel-11602: C, 79.96; H, 6.72. Found: C, 80.09; H,6.74.

Since the normal rearrangement product is a very sensitive substance itis advantageously protected as formed by acetylation. A mixture of 3. g.of the diallyl ether, 3 cc. of diethylaniline, and 3 cc. of aceticanhydride is heated at 200-210 in an atmosphere of nitrogen for 5-6hours. The cooled mixture is taken into ether and the solution extractedwith dilute hydrochloric acid, dried, and evaporated to a small volume.0n slow cooling 2,3-diallyl-1,4-naphthohydroquinone diacetate separatesas large, hexagonal prisms; yield 3.2 g. The substance is readilysoluble in benzene or alcohol, and moderately soluble in ligroin.Recrystallized from ether-petroleum ether or from ligroin (B. P. 70-90)it formed large, colorless prisms, M. P.

Anal.Calcd. for 0201-12004: C, 74.05; H, 6.22. Found C, 74.18; H, 6.33.1

The diacetate'is resistant to hydrolysisby alkalies and considerablematerial is recovered unchanged after boiling for several hours with12%" best results the diacetate is cleaved with Grignard reagent havinglittle reducing action. To the Grignard solution prepared under nitrogenfrom 3 g. of magnesium, 100 cc. of absolute ether and sufficient methylbromide to give complete reaction, is added 2.86 g. of 2,3-diallyl-1,4-naphthohydroquinone diacetate. The solution-is'refluxed for 45minutes, the ether is largely'replaced with dry benzene, and afterrefluxing for one-half hour longer the mixture is decomposed with 25%ammonium chloride solution and a little acid. The organic layer iswashed and dried and stirred mechanically with 2.05 g. of silver oxideand 10 g. ofv Dryrite for 10-15 minutes. The filtered, yellow solutionis concentrated, eventually under nitrogen, and the residual, darkyellow oil is cooled well and caused to solidify. After twocrystallizations from 95% alcohol (collecting the crystals in the coldroom) the substance forms glistening yellow blades, M. P. 29-30.

AnaL-Calcd. for Ciel-114022 C, 80.65; H, 5.92. Found C, 80.53; H, 6.02.Y The quinone is Very readily soluble in ether or petroleum ether,readily soluble in alcohol, spar,- ingly soluble in water. It gives ayellow or brown solution in concentrated sulfuric acid. A highlycharacteristic color test is obtained by adding a drop of 10% aqueouspotassium hydroxide to a. dilute solution of the quinone in alcohol; thesolution becomes pale greenish blue, then deep blue, which slowly fadesto a dull, weak green-brown.

Cleavage of 2,3-diallyl-1,4-naphthohydroqui-.

thoquinone derivative (maxima at 245, 267, and

330 m probably hydrogen has added to the side chain structure, eitherwith or without formation of an additional ring.

(4) 2,3-diaZlyl-6,7-dimethyl- 1,4 naphthoquinone.-Hydroquinone isconverted to the known diallyl ether [Hahn and Stenner, Z. physiol.Chem. 181, 88 (1929)]. more satisfactorily by the following method thanby that previously described. A. mixture of 44 g. of hydroquinone, 200cc. of acetone, 96.8 g. of allyl bromide, and 112 g. of potassiumcarbonate is refluxed for 9 hours, water is added to dissolve theinorganic salts, and the reaction product is extracted with ether.Phenolic material is extracted completely with 1 N sodium hydroxide andthe ethereal solution is dried and the solvent evaporated. The oilyresidue is induced to crystallize from a solution in dilute alkali bycooling and scratching, giving 52- g. of colorless, lustrous plates,

ML'P. 33-34; 5 g. of yellowish material is obalmost colorless materialwas washed with petroleum etherv to remove most of the kerosene. anddried at 50; yield, 57.5 g. ii I i Twoisomers are separatediromthis-mixture as follows. The material is largely dissolved by heatingwith 2 liters of water containing a little sodium hydrosulfite .andsteamdistilled to remove kerosene still present. A considerable amountof material remains undissolved as an oily solid. The hot solutionis'filtered, and on cooling the clean filtrate a large crop of2,5-diallylhydroquinone separates in a crystalline condition. Aftercollecting this the mother liquid is used to extract a fruther quantityof material from the semi-solid residue. After heating to boiling, thesolutionis separated from a small amount of darkbrown oil by filtrationand a sectained in a second crop, making the total yield 0nd crop ofthe-2,5-isomer obtained 'on cooling. The total yield of this isomer is25g; recrystali-ization from 2.1iters of water gave 15.2 g- (29%) ofpure product in the form of broad flat needles, M. P. 129.5-131.

Anal.-Calcd. for -C12H14O2: C, 75.76; H, 7.42. Found, C, 75.80; H, 7.40.

The combined aqueous mother liquors remaining after removal of the2,5-isomer on extraction with ethergive 22.2 g. of colorless crystallinematerial consisting largely of 2,3-diallylhydroquinone. This is verysoluble in hot water, but crystallizes satisfactorily from this solventin fine, colorless needles, M. P. 87-90.

Anal.Calcd. for C12H1402Z C, 75.76; H, 7.42 Found: C, 76.17; H, 7.60. 1

For oxidation 2.5 g. of 2,3-diallylhydroquinone is dissolved in 125 cc.of absolute ether and the solution stirred mechanically under nitrogenfor 3 hours with 6.3 g. of silver oxide and 6.5 g. of sodium sulfate.The yellow solution'is =evaporated, leaving a residue of2,3-dia1lyl-1,4-benzo'- quinone as a dark reddish yellow oil (2.4 g.),which is used directly for the next step.

A solution of 2.44 g. of 2,3-diallyl-1,4-benzoquinone and 3.4 cc. of2,3-dimethylbutadiene in 3 cc. of benzene is refluxed for 20 hours. Thediene addition product crystallizeson cooling and it is at onceisomerized to 6,7-dimethyl-2,3-dial1yl-5,8-dihydro-1,4-naphthohydroquinone by short boiling with dilutealcoholic hydrochloric acid. The brown product when crystallized fromalcohol melts at 156.5159 (yield, 2.34 g.). It can alsobe obtained byconducting the diene reaction in a sealed tube at 100 for 5 hoursandrefiuxing the product withdilute alcoholic hydrochloric acid.

AnaZ.Calcd. for Ciel-122022 C, 79.96; H, 8.20. Found: C, 80.27; H, 8.15.

A solution of 0.5 g. of the above hydroquinone in glacial acetic acid istreated at room temperature with a solution of 0.25 g. of chromicanhydrid'e in 10 cc. of 90% acetic acid. A rapid reaction ensues and thetemperature rises to about 44. After being heated to 60 and allowed tocool, the solution is diluted with Water and the dull yellow quinonewhich separates is purified by crystallization from alcohol; yield, 0.4g. It forms rectangular plates, M. P. 54-56 (sinterin'g at 50) andappears to be intermediate in degree of oxidation between the startingmaterial and the naphthoquinone derivative.

AnaZ.--Calcd. for (0181-11902) m1 Found: C, 80.80; H, 7.17.

For further oxidation 1 g. of the intermediate in 20 cc. of glacialacetic acid is treated with 0.3

g. of chromic anhydride and heated to when the temperature risesspontaneously to the solution finally is warmed to 100 and allowed tocool. The yellow material which precipitates on diluting with water iscrystallized from alcohol givingilong fiat needles or rectangular platesof. 2,3-'diallyl-6,7-dimethyl-1,4-naphthoquinone. Both forms are brightyellow and melt at 69.5- 70.7 absorption maxima: 253, 260, 273, 278, 343

AnaL-Calcd. for CmHmOz: Found: C, 81.46; H, 6.96.

'(5) 2,3-diallyl-1,4-naphthoquinone. Method b..The starting material forthis synthesis is monobutadiene-p-benzoquinone [Diels and Alder, Ben,62, 2337 (1929)]. A mixture of 7 g. of this additionproduct, 23.8 g. offinely powdered potassium carbonate, 10 cc. of allyl bromide, and 150cc. of purified acetone is refluxed overnight, diluted with water andextracted with ether. Phenolic material is removed by two washings withalkali containing sodium hydrosulfite, and the light yellow etherealsolution is washed with water, dried with calcium chloride, andevaporated, eventually with suctlon. The residue is taken up in warmmethanol and on cooling the product crystallizes. When washed withmethanol the 5,8-dihydro-1,4-naphthohydroquinone diallyl ether isobtained as colorless, pearly plates, M. P. 63-64 yield, 5.6 g.Recrystallized twice from alcohol, in which it is readily soluble, the.ether melts at 64-.-65.

AnaZ.Calcd. for CrcHmOz: C, 79.30; H, 7.49. Found: 0,7951; H, 7.55.

The ether is rearranged to 2,3-diallyl-5,8- dihydro 1,4naphthohydroquinone by heating 5.6 g. of material in 34 cc. of keroseneunder nitrogen in, a bath maintained at 240-250 for 2 hours. .Oncooling, still in a nitrogen atmosphere, the product separates as acrystalline paste. It is collected, washed with petroleum .ether, inwhich itis sparingly soluble, and obtained as completely colorlessplates, M. P. 107108.5; yield 4.9 g. The substance is moderately solublein ligroin (B, F. 70-90?) and crystallizes from this solvent in clustersof microcrystals. The solution turns slightly yellow and the crystalsacquire 'a pale-tan color. The purified compound melts at 108-109".Anal.Calcd. for CmHmO: C, 79.30; H, 7.49. Found: .C, 79.36; H, 7.78.

,- :Oxidation is conducted in'stages as in Example 4, using 4.35 g. ofthe dihydrohydroquinone in 25 cc. of acetic acid and 4.35 g. of chromicanhydride. After warming to 50 to start the reaction, the temperature isinitially kept from rising. above 70 by external cooling. the mixture isheated to 100, cooled, diluted with water, and the oily productextracted with ether.

.After washing with water and drying, the solvent is evaporated, leavingthe intermediate quinone asa yellow oil. Crystals are obtained bycooling to 78, and the product is then recrystallized from alcohol, andobtainedas bright yellow, rectangular tablets, M. .P. 19.5-21"(sintering at Finally Anal.Calcd. for (Cl6H1502):rI c, 8031i a:-

:cc. of. glacial acetic acid is conducted with 1 g.

oi chromic anhydride at 160-90", and the collected product '(2 g.),being part liquid and part solid, is oxidized again as before, when anexothermic reaction is noted at -90. The product recovered by etherextraction as above is obtained as a yellow oil which is induced tocrystallize by cooling a solution in alcohol in a bath of solid carbondioxide. The 2,3-diallyl-l,4-naphthoquinone then can be recrystallizedreadily from alcohol and forms long rectangular, bright yellow plates,M. P. 28.2-29.5. It did not depress the melting point of the sampleprepared by the synthesis given in Example 3.

I claim as my invention:

1. 2-allyl-1,4-naphtl1oquinone.

2. 3,7-dimethyl-2-allyl-1,4-naphthoquinone.

. 3. In a process for the preparation of 1,4- naphthoquinonessubstituted in the 2 and 3 positions by beta alkenyl groups the stepsconsisting in heating at ZOO-300 C. a di-beta alkenyl ether ofl,4-naphthohydroquinone, isolating the product of the resultingrearrangement as the diacetate and cleaving the diacetate by interactionwith a Grignard reagent.

4. Process as defined in claim 3 in which the beta alkenyl group is anallyl group.

5. In a process for the synthesis of 1,4-naphthoquinones having a betaalkenyl group in the quinone ring the steps consisting in heating at200-300" C. a l-naphthol ether of a beta unsaturated alcohol, saidalcohol being unsubstituted in at least the 2- and 4-positions, andintroducing into the 4-position of the resulting C-alkenyl naphthol anamino group by coupling with a diazotized amine and reduction.

6. Process as defined in claim 5 in which the beta alkenyl'group is anallyl group.

7. Process for the synthesis of 1,4-naphthoquinones having at least onebeta alkenyl group in the quinone ring consisting in heating at 200- 300C. a l-naphthol ether of a beta unsaturated alcohol, said alcohol beingunsubstituted in at least the 2-position and having a member of thegroup consisting of hydrogen, and a beta unsaturated alkenyl oxy groupin the 4position, and converting the resulting naphthol compound to thenaphthoquinone by coupling with diazotized sulfanilic acid, reducing theresulting azo compound to the corresponding amine and oxidizing saidamine to the corresponding quinone.

8. In a process for the synthesis of 1,4-naphthoquinones having at leastone beta alkenyl group in the quinone ring, the step which consists inheating at 200-300 C. a l-naphthol ether of a beta unsaturated alcoholof the group consisting of l-alkenyloxy and 1,4-dialkenyloxy derivativesof naphthalene.

9. A compound of the formula wherein R and R. each is a member 01' thegroup consisting of hydrogen and methyl.

LOUIS F. FIESER.

